The clinical significance of malfunction of the CD44 locus in malignancy

Conclusions This brief overview indicates that a large amount of intriguing information has emerged in the last few years about the unusual activity of the CD44 gene in neoplasia. It is a large gene and potentially could produce the most alternative splicing combinations yet described for any locus [1]. Although it is not yet known whether some of these are biologically inadmissable, several different isoforms containing various exon combinations have so far been detected. Therefore, it is likely that unravelling whether the observed disturbances in its regulation are causally involved in tumour induction and/or progression, or are merely consequences of other events, will take much time and effort.From a clinical standpoint the observations already made by several independent groups indicate that derangements at the CD44 locus may be sufficiently frequent and consistent to be a useful marker for early detection of certain types of malignancy. Further studies will establish whether or not there is a direct link between expression of certain CD44 splice variants and tumour invasion or metastasis. The results could have implications for evaluation of prognosis of individual patients in clinical work, but it is too early to comment further. Given that many genes show tissue specific patterns of expression in adult organs, it is possible that the detection of abnormal CD44 activity may only have clinical utility for tumour detection in some sites and not others. Even so, the results which have accumulated to date indicate that further investigation of the pleomorphic activities of this unusual gene may provide data which illuminate the pathogenesis of aggressive neoplastic behaviour. The clinical challenge is to try to convert the fundamental and promising information so far obtained into practical advances in the early diagnosis and treatment of malignancy.     

Tumourigenic transformation of mouse NIH 3T3 cells by transfection with plasmid pSV2neo

This study reports high incidence tumourigenic activity of the pSV2neo plasmid demonstrated by transfection of NIH 3T3 cells. The plasmid is frequently used as a dominant selectable marker for confirming successful gene transfection, and the findings indicate a need for caution in interpretation and design of assays for oncogenes which use co-transfection and subsequent selection with neomycin.     

Do the fastest concepti have a shorter life span?

An evolutionary hypothesis based on an 'antagonist pleiotropy' or 'disposable soma' mechanism is put forward to explain differences in longevity between species, strains, and sexes. Data from several congenic mouse strains and mammalian species suggest that there may be an association between cleavage rate of concepti and longevity, in such a way that concepti from species, strains or the sex (male) with the fastest cleavage rates have shorter life spans. The major histocompatibility complex (MHC) and, in particular, the conceptus development gene (Ped) together with several Y-linked genes that are expressed during the preimplantation stages of development may play an important role in determining or modulating longevity in mammals. Notwithstanding, effects of other loci as well as environmental factors on conceptus development and longevity cannot be ignored.      

Detection of telomerase activity in exfoliated cancer cells in colonic luminal washings and its related clinical implications.

Telomerase is a ribonucleoprotein capable of replacing telomeric DNA sequences that are lost at each cell division. Under normal circumstances, it is active in rapidly dividing embryonic cells and in stem cell populations but not in terminally differentiated somatic cells. Much attention has recently focused on the hypothesis that activity of this enzyme is necessary for cells to become immortal. This predicts that telomerase activity should be detectable in malignant cells and tissues but not in their normal counterparts, which slowly senesce and die. In accordance with this notion, telomerase activity has been reported in a wide range of malignancies, including those of the gastrointestinal tract, breast and lung. In the present study, we used a polymerase chain reaction (PCR)-based assay for telomerase activity, designated the "telomeric repeat amplification protocol (TRAP)'', to examine initially 35 colonic carcinomas, their corresponding normal tissues and 12 inflammatory bowel disease (IBD) lesions. We detected strong enzyme activity in 32 (92%) of the 35 colon carcinomas while there was no activity in 30 (86%) of 35 matched normal colonic tissue specimens and only very weak activity in the remainder. Four of seven specimens of ulcerative colitis and two of five Crohn''s disease lesions were negative, and the rest were only weakly positive. These results led us to examine whether telomerase could be detected in carcinoma cells exfoliated into the colonic lumen. We assayed lysates of exfoliated cells in luminal washings from colectomy specimens of 15 patients with colon carcinoma and nine with IBD. Telomerase activity was detected in washings from 9 (60%) of the 15 colon carcinoma cases but not in any from cases with IBD, suggesting that it can be a good marker for the detection of colon carcinoma, possibly even in non-invasively obtained samples.     

Tailored immunoconjugate therapy depending on a quantity of tumor stroma

The purpose of this study was to clarify the appropriate combination of targeting antibody and conjugate‐design of anti‐tumor immunoconjugate depending on a quantity of tumor stroma. Most human solid tumors including pancreatic cancer (PC) forming hypovascular and stroma‐rich tumor hinders the penetration of monoclonal antibodies (mAbs) into the cells, and that leads to failure of the conventional cell‐targeting immunoconjugate strategy. To overcome this drawback, SN‐38 as topoisomerase 1 inhibitor was conjugated to a mAb to collagen 4, a plentiful component of the tumor stroma via ester‐bond. The immunoconjugate, which was able to release SN‐38 in physiological condition outside the cells, was effective to stroma‐rich PC‐tumor. On the other hand, anti‐CD 20 mAb‐PEG‐SN‐38 via carbamate‐bond as conventional immunoconjugate, enabled SN‐38 to be released by a carboxylesterase inside of the tumor cell following the internalization, showed strong anti‐tumor activity against malignant lymphoma as hypervascular and stroma‐poor tumor. The conjugate‐design, in parallel with the choice of targeting antibodies, should be selected to maximize the therapeutic effect in each individual tumor having a distinct stromal structure.     

Policy process for health sector reforms: a case study of Punjab Province (Pakistan)

The health sector in the Punjab (Pakistan) faces many problems, and, the government introduced reforms during 1993–2000. This paper explores the policy process for the reforms. A case study method was used and, to assist this, a conceptual framework was developed. Analysis of four initiatives indicated that there were deviations from the government guidelines and that the policy processes used were weak. The progress of different reforms was affected by a variety of factors: the immaturity of the political process and civil society, which together with innate conservatism and resistance to change on the part of the bureaucracy resulted in weak strategic sectoral leadership and a lack of clear purpose underpinning the reforms. It also resulted in weaknesses in preparation of the detail of reforms leading to poor implementation. The study suggests a need for broadening the stakeholders' base, building the capacity of policy‐makers in policy analysis and strengthening the institutional basis of policymaking bodies. Copyright © 2009 John Wiley & Sons, Ltd.     

Review of significant microvascular surgical breakthroughs involving the heart and lungs in rats

Models of transplantation of the heart and lung in the rat have been important in determining the mechanisms of rejection and their treatment. Reviewed here are several important milestones contributing to the current state of the art of clinical heart and lung transplantation.     

The fallacy of epithelial mesenchymal transition in neoplasia

Epithelial mesenchymal transition has been postulated as a versatile mechanism which facilitates cellular repositioning and redeployment during embryonic development, tissue reconstruction after injury, carcinogenesis, and tumor metastasis. The hypothesis originates from parallels drawn between the morphology and behavior of locomotory and sedentary cells in vitro and in various normal and pathologic processes in vivo. This review analyzes data from several studies on embryonic development, wound healing, and the pathology of human tumors, including work from our own laboratory, to assess the validity of the proposal. It is concluded that there is no convincing evidence for conversion of epithelial cells into mesenchymal cell lineages in vivo and that the biological repertoire of normal and malignant cells is sufficient to account for the events and processes observed, without needing to invoke radical changes in cell identity.